Cardiac Function Heart Failure Research Articles

Ginsenoside Rb1 ameliorates heart failure through DUSP-1-TMBIM-6-mediated mitochondrial quality control and gut flora interactions

BackgroundThere is currently no specific therapeutic drug available for heart failure in clinical practice. Numerous studies have validated the efficacy of Ginsenoside Rb1, an active component found in various herbal remedies used for heart failure treatment, in effectively ameliorating myocardial ischemia. However, the precise mechanism of action and molecular targets of Ginsenoside Rb1 remain unclear. PurposeThis study aims to explore the molecular mechanisms through which Ginsenoside Rb1 synergistically modulates the gut flora and mitochondrial quality control network in heart failure by targeting the DUSP-1-TMBIM-6-VDAC1 axis. Study DesignThis study utilized DUSP-1/VDAC1 knockout (DUSP-1-/-/VDAC1-/-) and DUSP-1/VDAC1 transgenic (DUSP-1+/+/VDAC1+/+) mouse models of heart failure, established through Transverse Aortic Constriction (TAC) surgery and genetic modification techniques. The mice were subsequently subjected to treatment with Ginsenoside Rb1. MethodsA series of follow-up multi-omics analyses were conducted, including assessments of intestinal flora, gene transcription sequencing, single-cell databases, and molecular biology assays of primary cardiomyocytes, to investigate the mechanism of action of Ginsenoside Rb1. ResultsGinsenoside Rb1 was found to have multiple regulatory mechanisms on mitochondria. Notably, DUSP-1 was discovered to be a crucial molecular target of Ginsenoside Rb1, controlling both intestinal flora and mitochondrial function. The regulatory effects of DUSP-1 on inflammation and mitochondrial quality control were mediated by changes in TMBIM-6 and VDAC1. Furthermore, NLRP3-mediated inflammatory responses were found to interact with mitochondrial quality control, exacerbating myocardial injury under stress conditions. Ginsenoside Rb1 modulated the DUSP-1-TMBIM-6-VDAC1 axis, inhibited the release of pro-inflammatory factors, altered the structural composition of the gut flora, and protected impaired heart function. These effects indirectly influenced the crosstalk between inflammation, mitochondria, and gut flora. ConclusionThe DUSP-1-TMBIM-6-VDAC1 axis, an upstream pathway regulated by Ginsenoside Rb1, is a profound mechanism through which Ginsenoside Rb1 improves cardiac function in heart failure by modulating inflammation, mitochondria, and gut flora.

Association of Biological Age Acceleration with Cardiac Morphology, Function, and Incident Heart Failure: Insights from UK Biobank Participants.

Advanced age is associated with an increased risk of adverse cardiovascular events. The relationship between biological age acceleration (BAA), cardiac size, cardiac function, and heart failure (HF) is not well-defined. Utilizing the UK Biobank cohort, we assessed biological age using the Klemera-Doubal and PhenoAge method. BAA was quantified by residual analysis compared to chronological age. Cardiovascular magnetic resonance (CMR) imaging provided detailed insights into cardiac structure and function. We employed multivariate regression to examine links between BAA and CMR-derived cardiac phenotypes. Cox proportional hazard regression models analyses was applied to explore the causative relationship between BAA and HF. Additionally, Mendelian randomization was used to investigate the genetic underpinnings of these associations. A significant correlation was found between increased BAA and deleterious changes in cardiac structure, such as diminished left ventricular mass, lower overall ventricular volume, and reduced stroke volumes across ventricles and atria. Throughout a median follow-up of 13.8 years, participants with greater biological aging showed a heightened risk of HF (26% per standard deviation [SD] increase in KDM-BA acceleration, 95% confidence intervals [CI]: 23%-28%; 33% per SD increase in PhenoAge acceleration, 95% CI: 32%-35%). Mendelian randomization analysis suggests a likely causal link between BAA, vital cardiac metrics, and HF risk. In this cohort, accelerated biological aging may serve as a risk indicator for altered cardiac dimensions, functionality, and the onset of heart failure among middle-aged and elderly adults. It holds promise as a focal point for evaluating risk and developing targeted interventions.

Urinary Proteomics and Outcomes in Heart Failure With Preserved Ejection Fraction.

Although several studies have addressed plasma proteomics in heart failure with preserved ejection fraction, limited data are available on the prognostic value of urinary proteomics. The objective of our study was to identify urinary proteins/peptides associated with death and heart failure admission in patients with heart failure with preserved ejection fraction. The study population included participants enrolled in TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial). The relationship between urine protein levels and the risk of death or heart failure admission was assessed using Cox regression, in both nonadjusted analyses and adjusting for urine creatinine levels, and the MAGGIC (Meta-Analysis Global Group in Chronic Heart Failure) score. A total of 426 (12.4%) TOPCAT participants had urinary protein data and were included. There were 40 urinary proteins/peptides significantly associated with death or heart failure admission in nonadjusted analyses, 21 of which were also significant adjusted analyses. Top proteins in the adjusted analysis included ANGPTL2 (angiopoietin-like protein 2) (hazard ratio [HR], 0.5731 [95% CI, 0.47-0.7]; P=3.13E-05), AMY2A (α amylase 2A) (HR, 0.5496 [95% CI, 0.44-0.69]; P=0.0001), and DNASE1 (deoxyribonuclease-1) (HR, 0.5704 [95% CI, 0.46-0.71]; P=0.0002). Higher urinary levels of proteins involved in fibrosis (collagen VI α-1, collagen XV α-1), metabolism (pancreatic α-amylase 2A/B, mannosidase α class 1A member 1), and inflammation (heat shock protein family D member 1, inducible T cell costimulatory ligand) were associated with a lower risk of death or heart failure admission. Our study identifies several novel associations between urinary proteins/peptides and outcomes in heart failure with preserved ejection fraction. Many of these associations are independent of clinical risk scores and may aid in risk stratification in this patient population.

Estimated pulse wave velocity predicts mortality in patients with heart failure with preserved ejection fraction

ObjectiveEstimated pulse wave velocity (ePWV), a newly established arterial stiffness (AS) parameter, predicts the development of cardiovascular disease (CVD) and death in the general population or in patients with CVD risk factors. However, whether ePWV is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF) patients remains unknown. Our study aimed to evaluate the prognostic value of ePWV on clinical outcomes in HFpEF. Methods and ResultsWe analyzed HFpEF participants from the Americas in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with available baseline data (n = 1764). Cox proportional hazard model was used to explore the prognostic value of ePWV on long-term clinical outcomes (all-cause mortality, cardiovascular mortality, all-cause hospitalization, and heart failure hospitalization). Each ePWV increase by 1 m/s increased the risk for all-cause death by 16% (HR:1.16; 95% CI:1.10–1.23; P < 0.001) and CVD mortality by 13% (HR:1.13; 95% CI:1.04–1.21; P = 0.002) after adjusting for confounders. Patients were then grouped into 4 quartiles of ePWV. Our study indicated that the highest ePWV quartile (ePWV ≥ 12.806 m/s) was associated with increased risk of all-cause mortality (HR: 1.96; 95% CI: 1.43–2.69; P < 0.001) and CVD mortality (HR: 1.72; 95% CI: 1.16–2.56; P = 0.008) after adjusting for potential confounders. ConclusionThese results suggested ePWV is independently associated with increased all-cause mortality and CVD mortality in HFpEF patients, indicating ePWV is an appropriate predictor of prognosis in patients with HFpEF.

Prognostic Value of Depressive Symptoms for Cardiovascular Events in Female Patients With Heart Failure With Reduced Ejection Fraction and Heart Failure With Preserved Ejection Fraction.

Among those with heart failure (HF), women are more likely to develop depression than men. Few studies have focused on the outcomes of female patients with HF with depressive symptoms. A total of 506 female patients with HF with preserved ejection fraction were included in this secondary analysis from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) cohort, and 439 female patients with HF with reduced ejection fraction were included from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) cohort. Depressive symptoms were measured using the Patient Health Questionnaire-9 and Beck Depression Inventory-II. The depression class was categorized by severity, and the change in clinical depression class was defined as aggravated (1-grade increase) or improved (1-grade decrease). The prognostic value of depressive symptoms was determined by using multivariable Cox proportional hazards models. Female patients with improved depressive symptoms had worse depressive status at baseline and lower baseline Kansas City Cardiomyopathy Questionnaire scores. Depression class at the 12-month visit and depression class change were the dominant prognostic factors for cardiovascular death in female patients with HF with preserved ejection fraction (hazard ratio [HR], 1.43 [95% CI, 1.02-2.01], P=0.036; HR, 1.71 [95% CI, 1.14-2.55], P=0.009). Among the patients with HF with reduced ejection fraction, both the depression class at baseline and depression class change had significant prognostic effects on cardiovascular death (HR, 3.30 [95% CI, 1.70-6.39], P<0.001; HR, 2.21 [95% CI, 1.28-3.80], P=0.004). However, the prognostic value of depressive assessments for hospitalization in patients with HF is unclear. In female patients with HF with reduced ejection fraction, the depression class at baseline was most strongly associated with cardiovascular death, whereas in female patients with HF with preserved ejection fraction, the change in depression class exhibited a more significant prognostic trend.

Individualized Treatment Effect Prediction with Machine Learning — Salient Considerations

BackgroundMachine learning–based approaches that seek to accomplish individualized treatment effect prediction have gained traction; however, some salient challenges lack wider recognition.MethodsWe describe key methodologic considerations for individualized treatment effect prediction models using data from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial for spironolactone in heart failure with preserved ejection fraction. The causal survival forest algorithm was used for model development. Calibration and discrimination were evaluated using a bootstrapping-based internal validation procedure. Observed benefits were described for predicted benefit quartiles and quartiles of a known effect modifier: ejection fraction. A negative control analysis with noncardiovascular death as the outcome was implemented to detect confounding.ResultsAmong 3445 participants, 671 events occurred over a median of 3.3 years of follow-up. In internal validation, a higher average observed benefit was noted among patients in the highest quartile of predicted benefit. The median (interquartile range) of the observed restricted mean survival time difference at 3.3 years at the highest quartile of model-predicted benefit was 62 days (32 to 83) and was 47 days (26 to 67) at the lowest quartile of ejection fraction. Body-mass index had higher contribution to prediction of benefit relative to other included measures (33.7% vs. glomerular filtration rate [27.3%], ejection fraction [15.1%], and younger age [12.8%]) No benefit was observed for noncardiovascular death at higher model-predicted benefit quartiles, although benefit for noncardiovascular death was observed at lower quartiles.ConclusionsCarefully applied and validated predictive models hold promise in identifying heterogeneous treatment effects and are useful for hypothesis generation regarding the role of phenotypic characteristics in modifying the benefit of experimental interventions in clinical trials. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00094302.)

Nonclinical evaluation of chronic cardiac contractility modulation on 3D human engineered cardiac tissues.

Cardiac contractility modulation (CCM) is a medical device-based therapy delivering non-excitatory electrical stimulations to the heart to enhance cardiac function in heart failure (HF) patients. The lack of human in vitro tools to assess CCM hinders our understanding of CCM mechanisms of action. Here, we introduce a novel chronic (i.e., 2-day) in vitro CCMassay to evaluate the effects of CCM in a human 3D microphysiological system consisting of engineered cardiac tissues (ECTs). Cryopreserved human induced pluripotent stem cell-derived cardiomyocytes were used to generate 3D ECTs. The ECTs were cultured, incorporating human primary ventricular cardiac fibroblasts and a fibrin-based gel. Electrical stimulation was applied using two separate pulse generators for the CCM group and control group. Contractile properties and intracellular calcium were measured, and a cardiac gene quantitative PCR screen was conducted. Chronic CCM increased contraction amplitude and duration, enhanced intracellular calcium transient amplitude, and altered gene expression related to HF (i.e., natriuretic peptide B, NPPB) and excitation-contraction coupling (i.e., sodium-calcium exchanger, SLC8). These data represent the first study of chronic CCM in a 3D ECT model, providing a nonclinical tool to assess the effects of cardiac electrophysiology medical device signals complementing in vivo animal studies. The methodology established a standardized 3D ECT-based in vitro testbed for chronic CCM, allowing evaluation of physiological and molecular effects on human cardiac tissues.

Association of hypertension burden with stroke risk in patients with heart failure with preserved ejection fraction

IntroductionWhether the hypertension burden is associated with stroke incidence is inconclusive. In this study, we aimed to investigate the relationship between hypertension burden and stroke risk in patients with heart failure with preserved ejection fraction (HFpEF). MethodsHFpEF patients from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial were divided into three groups (low, medium, and high risk) according to their hypertension burden values. Higher hypertension burden risk represented the longer duration of hypertension. We evaluated the association of hypertension burden with stroke risk using Fine and Gray's competing risk models. ResultsA total of 3431 HFpEF patients (mean age: 68.5 ± 9.58 years, 51.6% females) were enrolled. During a median follow-up of 3.3 years, per 10-point increase in hypertension burden was associated with any stroke (hazard ratio [HR] 1.15, 95% confidence interval [CI] 1.08–1.21), new-onset stroke (HR 1.14, 95% CI 1.07–1.21), and ischemic stroke (HR 1.10, 95% CI 1.02–1.17). When hypertension burden was analyzed as a categorical variable, any stroke risk was increased in the medium- (HR 1.59, 95% CI 1.01–2.40) and high-risk (HR 3.19, 95% CI 2.05–4.97) groups when compared with the low-risk group. For the outcomes of new-onset (HR 2.92, 95% CI 1.80–4.74) and ischemic stroke (HR 2.46, 95% CI 1.41–4.29), similar results were observed in patients with high-versus low-risk hypertension burden. ConclusionsIncreasing hypertension burden was associated with an increased risk of stroke, suggesting that shortening hypertension duration might appropriately minimize the stroke incidence in HFpEF patients.

Downregulation of the CD151 protects the cardiac function by the crosstalk between the endothelial cells and cardiomyocytes via exosomes.

Heart failure (HF) is the last stage in the progression of various cardiovascular diseases. Although it is documented that CD151 contributes to regulate the myocardial infarction, the function of CD151 on HF and involved mechanisms are still unclear. In the present study, we found that the recombinant adeno-associated virus (rAAV)-mediated endothelial cell-specific knockdown of CD151-transfected mice improved transverse aortic constriction (TAC)-induced cardiac function, attenuated myocardial hypertrophy and fibrosis, and increased coronary perfusion, whereas overexpression of the CD151 protein aggravated cardiac dysfunction and showed the opposite effects. In vitro, the cardiomyocytes hypertrophy induced by PE were significantly improved, while the proliferation and migration of cardiac fibroblasts (CFs) were significantly reduced, when co-cultured with the CD151-silenced endothelial cells (ECs). To further explore the mechanisms, the exosomes from the CD151-silenced ECs were taken by cardiomyocyte (CMs) and CFs, verified the intercellular communication. And the protective effects of CD151-silenced ECs were inhibited when exosome inhibitor (GW4869) was added. Additionally, a quantitative proteomics method was used to identify potential proteins in CD151-silenced EC exosomes. We found that the suppression of CD151 could regulate the PPAR signaling pathway via exosomes. Our observations suggest that the downregulation of CD151 is an important positive regulator of cardiac function of heart failure, which can regulate exosome-stored proteins to play a role in the cellular interaction on the CMs and CFs. Modulating the exosome levels of ECs by reducing CD151 expression may offer novel therapeutic strategies and targets for HF treatment.

Proteomic Associations of NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) in Heart Failure With Preserved Ejection Fraction.

NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels are variably elevated in heart failure with preserved ejection fraction (HFpEF), even in the presence of increased left ventricular filling pressures. NT-proBNP levels are prognostic in HFpEF and have been used as an inclusion criterion for several recent randomized clinical trials. However, the underlying biologic differences between HFpEF participants with high and low NT-proBNP levels remain to be fully understood. We measured 4928 proteins using an aptamer-based proteomic assay (SOMAScan) in available plasma samples from 2 cohorts: (1) Participants with HFpEF enrolled in the PHFS (Penn Heart Failure Study; n=253); (2) TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) participants in the Americas (n=218). We assessed the relationship between SOMAScan-derived plasma NT-proBNP and levels of other proteins available in the SOMAScan assay version 4 using robust linear regression, with correction for multiple comparisons, followed by pathway analysis. NT-proBNP levels exhibited prominent proteome-wide associations in PHFS and TOPCAT cohorts. Proteins most strongly associated with NT-proBNP in both cohorts included SVEP1 (sushi, von Willebrand factor type-A, epidermal growth factor, and pentraxin domain containing 1; βTOPCAT=0.539; P<0.0001; βPHFS=0.516; P<0.0001) and ANGPT2 (angiopoietin 2; βTOPCAT=0.571; P<0.0001; βPHFS=0.459; P<0.0001). Canonical pathway analysis demonstrated consistent associations with multiple pathways related to fibrosis and inflammation. These included hepatic fibrosis and inhibition of matrix metalloproteases. Analyses using cut points corresponding to estimated quantitative concentrations of 360 pg/mL (and 480 pg/mL in atrial fibrillation) revealed similar proteomic associations. Circulating NT-proBNP levels exhibit prominent proteomic associations in HFpEF. Our findings suggest that higher NT-proBNP levels in HFpEF are a marker of fibrosis and inflammation. These findings will aid the interpretation of NT-proBNP levels in HFpEF and may guide the selection of participants in future HFpEF clinical trials.

Body mass index, frailty, and outcomes in heart failure with preserved ejection fraction.

Relationship between body mass index (BMI), frailty, and clinical adverse events remains unclear in patients with heart failure (HF) with preserved ejection fraction (HFpEF) in different patient populations. We aimed to compare the association of BMI, frailty, and clinical adverse events between a US cohort from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study and a Chinese cohort from the Heart Failure Registry of Patient Outcomes (HERO) study. We used data of 1715 participants enrolled from America in the TOPCAT study and 1487 patients with HFpEF in the Chinese registry study, the HERO. We evaluated the relationship between BMI and frailty using multivariate restricted cubic spline logistic regression. Association between frailty and BMI categories and primary outcomes including HF hospitalization, aborted sudden death, and cardiovascular death, all-cause mortality, and HF hospitalization were analysed by Cox proportional hazards models. The patients' mean age was 72±11years for both study populations, with 50% and 46% female for the TOPCAT study and the HERO study, respectively. Patients in the TOPCAT study had a higher mean BMI (33.9 vs. 24kg/m2), with 72.3% vs. 52.9% defined as moderately to severely frail (frailty index>0.3). In the TOPCAT study, risk of frailty rose as BMI increased, but not in the HERO study. Patients with frailty were at significant higher risk for the primary composite outcomes [hazard ratio (HR) 1.84 (95% confidence interval: 1.46-2.32)], all-cause mortality [HR 1.73 (1.34-2.25)], and HF hospitalization [HR 1.83 (1.40-2.40)] in the TOPCAT study. The corresponding numbers in the HERO study were 1.26 (1.01-1.57), 2.21 (1.45-3.35), and 1.15 (0.81-1.37), respectively. The association of frailty with clinical outcomes did not vary with BMI categories in the two studies. BMI distribution and association between BMI and frailty risk were different between the two study populations. Frailty was associated with clinical adverse events and this association was consistent across different BMI categories in both studies.

The emerging concept of glycocalyx damage as the trigger of heart failure onset and progression

The suppression of adrenergic and renin-angiotensin-aldosterone system (RAAS) activity, exaggerated due to hypoperfusion-related hypoxia and/or sodium retention, is crucial for drugs’ efficacy in heart failure (HF). Both, insufficient oxygenation and excess sodium impair the glycocalyx-dependent microcroperfusion and peripheral metabolism, therefore enhancing the adrenergic and RAAS activity. The local renal and pulmonary RAAS activity and hypoxia increase sodium retention. Interstitial sodium accumulation activates interstitial inflammation and coagulation disorders that further diminish glycocalyx-supported microperfusion and peripheral metabolism. The main trigger of glycocalyx damage in reduced ejection fraction (EF) HF is hypoxia; whereas, in HF preserved EF sodium retention prevails; both stimulate left ventricular (LV) cardiac output (CO), however, impair microperfusion and metabolic heat production. Infrared-dependent, surface-induced flow (SIF) and diamagnetic properties of oxygenated haemoglobin; both improve non-Newtonian blood flow. Therefore, the temperature-driven SIF augments the deoxygenated erythrocytes' flow, while the pulmonary oxygenation of haemoglobin, by diamagnetic properties, enables frictionless erythrocytes’ flow in the oxygenated blood compartments complementing the cardiac function in HF.

Changes in adiponectin system after ventricular assist device in pediatric heart failure

Ventricular assist device (VAD) implant represents a therapeutic option for pediatric patients with end-stage heart failure (HF). Heart unloading by VAD can modify several molecular pathways underlying cardiac function in HF. Among them, the potential role of microRNA (miRNAs) in response to VAD implant is emerging. This study was aimed at investigating in HF pediatric patients the effect of VAD-modified miRNAs on the adiponectin (ADPN) system, known to exert cardioprotective actions. ADPN was measured in plasma samples obtained from HF children, before and 1month after VAD implant, and from healthy control children. miRNA profile and molecules belonging to ADPN system were determined in cardiac biopsies collected at the time of VAD implantation (pre-VAD) and at the moment of heart transplant (post-VAD). An in vitro study using HL-1 cell line was performed to verify the regulatory role of the VAD-modified miRNA on the ADPN system. VAD implant did not affect circulating and cardiac levels of ADPN, but increased the cardiac mRNA expression of ADPN receptors, including AdipoR1, AdipoR2, and T-cad. AdipoR2 and T-cad were inversely related to the VAD-modified miRNA levels. The in vitro study confirmed the regulatory role of miR-1246 and miR-199b-5p on AdipoR2, and of miR-199b-5p on T-cad. These data suggest that VAD treatment could regulate the expression of the cardioprotective ADPN system by epigenetic mediators, suggesting that miRNAs have a potential role as therapeutic targets to improve cardiac function in HF pediatric patients.

Recurrent heart failure hospitalizations in heart failure with preserved ejection fraction: an analysis of TOPCAT trial.

Recurrent heart failure hospitalization (HFH) is an important feature of the progression of heart failure (HF). In the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, we analysed risk factors for recurrent HFH events in HF patients with preserved ejection fraction (HFpEF) and developed a risk prediction model for recurrent HFH. This analysis focused on the subset of TOPCAT participants enrolled in the Americas (n=1767). Recurrent HFH was defined as two or more hospitalizations for HF during the follow-up period. Lasso regression and multivariate logistic regression were used to screen the risk factors, and the risk prediction model of recurrent HFH was established. During a median follow-up period of 3.4 (95% confidence interval: 3.3-3.6) years, 72.2% (542 of 751 total hospitalizations) of HFH events occurred in 9.4% (n=163) of patients with recurrent HFHs. Patients in the recurrent HFH group had higher cardiovascular mortality rate [6.2 per 100 patient-years (PY) vs. 3.8 per 100 PY, P=0.016] and all-cause mortality rate (10.0 per 100 PY vs. 6.8 per 100 PY, P=0.015) than those in the non-recurrent HFH group. The model consisting of nine predictors has moderate predictive power for recurrent HFH events in patients with HFpEF (AUC=0.75, Brier score=0.08). Decision curve analysis showed a net clinical benefit from the application of the prediction model. In patients with HFpEF, the majority of HFHs occur in a small proportion of patients with repeated hospitalizations, who typically have more comorbidities and are at higher risk of death. The predictive model developed in this study helps to identify patients at high risk of recurrent HFH.

Left bundle branch area pacing improves right ventricular function in heart failure with preserved ejection fraction: evidence from PROPHET trial

Abstract Background Left bundle branch area pacing (LBBAP) has emerged as a promising pacing strategy, especially for patients with heart failure. However, the impact of LBBAP on hemodynamics and cardiac function in heart failure with preserved ejection fraction (HFpEF) has not been investigated yet. Aim To investigate the hemodynamic response and change of cardiac function of LBBAP in patients with HFpEF. Methods This prospective cohort study enrolled patients with preserved left ventricular ejection fraction who were receiving LBBAP, and two cohorts (non-HFpEF cohort and HFpEF cohort) were built based on diagnosis of HFpEF. Hemodynamics before and after LBBAP were measured using right heart catheterization (RHC). And the changes of cardiac function were evaluated by transthoracic speckle tracking echocardiography (STE). Results 30 consecutive patients were included in the study, with 17 patients in the non-HFpEF group and 13 patients in the HFpEF group. Preprocedural STE showed worsened right ventricular function in the HFpEF group indicated by global longitudinal strain rate, free-wall strain rate, fractional area change, Tricuspid annular pulmonary systolic excursion and Tei index. And RHC showed elevated right ventricular stroke work index (RVSWI, 8.6±4.1 non-HFpEF vs 15.0±5.6 HFpEF, P = 0.170). While post-LBBAP evaluation showed a more significant reduction in RVSWI in the HFpEF group (6.7±2.5 (reduction 22.1%) non-HFpEF vs 8.0±1.0 (reduction 46.7%) HFpEF, P = 0.043). Besides, post-LBBAP STE showed improvement of right ventricular function, despite no significant difference in the extent of improvement was found between groups. Conclusion LBBAP might be more beneficial to patients with HFpEF as it could improve right ventricular function by alleviating the workload of right ventricle. Long-term benefit of LBBAP in HFpEF requires further investigation.

Exogenous NADPH exerts a positive inotropic effect and enhances energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure

Therapies are urgently required to ameliorate pathological cardiac hypertrophy and enhance cardiac function in heart failure. Our preliminary experiments have demonstrated that exogenous NADPH exhibits a positive inotropic effect on isolated heart. This study aims to investigate the positive inotropic effects of NADPH in pathological cardiac hypertrophy and heart failure, as well as the underlying mechanisms involved. Endogenous plasma NADPH contents were determined in patients with chronic heart failure and control adults. The positive inotropic effects of NADPH were investigated in isolated toad heart or rat heart. The effects of NADPH were investigated in isoproterenol (ISO)-induced cardiac hypertrophy or transverse aortic constriction (TAC)-induced heart failure. The underlying mechanisms of NADPH were studied using SIRT3 knockout mice, echocardiography, Western blotting, transmission electron microscopy, and immunoprecipitation. The endogenous NADPH content in the blood of patients and animals with pathological cardiac hypertrophy or heart failure was significantly reduced compared with age-sex matched control subjects. Exogenous NADPH showed positive inotropic effects on the isolated normal and failing hearts, while antagonism of ATP receptor partially abolished the positive inotropic effect of NADPH. Exogenous NADPH administration significantly reduced heart weight indices, and improved cardiac function in the mice with pathological cardiac hypertrophy or heart failure. NADPH increased SIRT3 expression and activity, deacetylated target proteins, improved mitochondrial function and facilitated ATP production in the hypertrophic myocardium. Importantly, inhibition of SIRT3 abolished the positive inotropic effect of NADPH, and the anti-heart failure effect of NADPH was significantly reduced in the SIRT3 Knockout mice. Exogenous NADPH shows positive inotropic effect and improves energy metabolism via SIRT3 in pathological cardiac hypertrophy and heart failure. NADPH thus may be one of the potential candidates for the treatment of pathological cardiac hypertrophy or heart failure. This work was supported by grants from the National Natural Science Foundation of China (No. 81973315, 82173811, 81730092), Natural Science Foundation of Jiangsu Higher Education (20KJA310008), Jiangsu Key Laboratory of Neuropsychiatric Diseases (BM2013003) and the Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD).

Echocardiographic characterization of patients with supranormal ejection fraction: pooled core laboratory analysis of the TOPCAT and PARAGON-HF trials

Abstract Background Patients with heart failure and supranormal ejection fraction (HFsnEF) may be phenotypically distinct from those with normal or below normal left ventricular ejection fraction (LVEF), and may demonstrate different prognostic trajectories or treatment responses. Purpose To characterize clinical features, cardiac structure and function among patients with HF with preserved EF (defined as 45% ≤ LVEF ≤ 65%) and supranormal EF (defined as LVEF&amp;gt;65%). Methods Baseline clinical characteristics and key echocardiographic parameters from patients enrolled in the echocardiographic substudies of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist)-Americas and PARAGON-HF (Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blocker] Global Outcomes in Heart Failure with Preserved Ejection Fraction) were compared between patients with and without HFsnEF. Results Among 1,751 participants (mean age 73 years old, 51% women) in this pooled core laboratory analysis, 265 (15%) had HFsnEF. Participants in HFsnEF group were more likely to be women, and less likely to have prior myocardial infarction and atrial fibrillation (Table 1). Compared with those with LVEF ≤ 65%, those with LVEF &amp;gt; 65% had lower LV end-diastolic and end-systolic volume indices, lower LV mass index, higher LV relative wall thickness, and higher right ventricular fractional area change. LV geometry and measures of LV diastolic function were similar in both groups (Table 1). Global longitudinal strain (GLS) was abnormal (absolute GLS &amp;lt;16%) in 28% in those with HFsnEF compared with 53% in those with LVEF ≤ 65%. After adjusting for baseline LV ejection fraction and sex, and stratified by trial, abnormal GLS was associated with a higher risk of composite of first heart failure hospitalization or cardiovascular death (overall hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.23 – 1.98, P &amp;lt; 0.001), cardiovascular death (overall HR 2.06, 95% CI 1.35 – 3.13, P = 0.001), and heart failure hospitalization (overall HR 1.49, 95% CI 1.15 – 1.93, P = 0.003) in both HFsnEF and non-HFsnEF groups (P-interaction &amp;gt; 0.05 for all, Figure 1). Conclusions Among participants in the TOPCAT-Americas and PARAGON-HF trials, those with LVEF &amp;gt; 65% were predominantly women, had less LV remodeling, and had better RV function based on echocardiographic measures. Nevertheless, despite supranormal LVEF, GLS was abnormal in over a quarter of patients and remained an important predictor of adverse clinical outcomes in this cohort.Table 1Figure 1

Abstract 14945: Left Bundle Branch Area Pacing Improves Right Ventricular Function in Heart Failure With Preserved Ejection Fraction: Evidence From PROPHET Trial

Introduction: Left bundle branch area pacing (LBBAP) has emerged as a promising pacing strategy, especially for patients with heart failure. However, the impact of LBBAP on hemodynamics and cardiac function in heart failure with preserved ejection fraction (HFpEF) has not been investigated yet. Hypothesis: LBBAP could improve cardiac function of patients with HFpEF. Methods: This prospective cohort study enrolled patients with preserved left ventricular ejection fraction who were receiving LBBAP, and two cohorts (non-HFpEF cohort and HFpEF cohort) were built based on diagnosis of HFpEF. Hemodynamics before and after LBBAP were measured using right heart catheterization (RHC). And the changes of cardiac function were evaluated by transthoracic speckle tracking echocardiography (STE) Results: 30 consecutive patients were included in the study, with 17 patients in the non-HFpEF group and 13 patients in the HFpEF group. Preprocedural STE showed worsened right ventricular function in the HFpEF group indicated by global longitudinal strain rate, free-wall strain rate, fractional area change, Tricuspid annular plane systolic excursion and Tei index. And RHC showed elevated right ventricular stroke work index (RVSWI, 8.6±4.1 non-HFpEF vs 15.0±5.6 HFpEF, P=0.170). While post-LBBAP evaluation showed a more significant reduction in RVSWI in the HFpEF group (6.7±2.5 (reduction 22.1%) non-HFpEF vs 8.0±1.0 (reduction 46.7%) HFpEF, P=0.043). Besides, post-LBBAP STE showed improvement of right ventricular function, despite no significant difference in the extent of improvement was found between groups. Conclusions: LBBAP might be more beneficial to patients with HFpEF as it could improve right ventricular function by alleviating the workload of right ventricle. Long-term benefit of LBBAP in HFpEF requires further investigation.

Elimination of CaMKIIδ Autophosphorylation by CRISPR-Cas9 Base Editing Improves Survival and Cardiac Function in Heart Failure in Mice.

Cardiovascular diseases are the main cause of worldwide morbidity and mortality, highlighting the need for new therapeutic strategies. Autophosphorylation and subsequent overactivation of the cardiac stress-responsive enzyme CaMKIIδ (Ca2+/calmodulin-dependent protein kinase IIδ) serves as a central driver of multiple cardiac disorders. To develop a comprehensive therapy for heart failure, we used CRISPR-Cas9 adenine base editing to ablate the autophosphorylation site of CaMKIIδ. We generated mice harboring a phospho-resistant CaMKIIδ mutation in the germline and subjected these mice to severe transverse aortic constriction, a model for heart failure. Cardiac function, transcriptional changes, apoptosis, and fibrosis were assessed by echocardiography, RNA sequencing, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, and standard histology, respectively. Specificity toward CaMKIIδ gene editing was assessed using deep amplicon sequencing. Cellular Ca2+ homeostasis was analyzed using epifluorescence microscopy in Fura-2-loaded cardiomyocytes. Within 2 weeks after severe transverse aortic constriction surgery, 65% of all wild-type mice died, and the surviving mice showed dramatically impaired cardiac function. In contrast to wild-type mice, CaMKIIδ phospho-resistant gene-edited mice showed a mortality rate of only 11% and exhibited substantially improved cardiac function after severe transverse aortic constriction. Moreover, CaMKIIδ phospho-resistant mice were protected from heart failure-related aberrant changes in cardiac gene expression, myocardial apoptosis, and subsequent fibrosis, which were observed in wild-type mice after severe transverse aortic constriction. On the basis of identical mouse and human genome sequences encoding the autophosphorylation site of CaMKIIδ, we deployed the same editing strategy to modify this pathogenic site in human induced pluripotent stem cells. It is notable that we detected a >2000-fold increased specificity for editing of CaMKIIδ compared with other CaMKII isoforms, which is an important safety feature. While wild-type cardiomyocytes showed impaired Ca2+ transients and an increased frequency of arrhythmias after chronic β-adrenergic stress, CaMKIIδ-edited cardiomyocytes were protected from these adverse responses. Ablation of CaMKIIδ autophosphorylation by adenine base editing may offer a potential broad-based therapeutic concept for human cardiac disease.

Abstract 14279: Improved Pressure-Flow Relationship With Sacubitril/Valsartan: A 6-min Walk Stress Echocardiographic Study

Background: In the clinical setting, there are various techniques for stress echocardiography, of which the 6-minute walk (6MW) test is a straightforward and utilized one. An abnormal hemodynamic response to exercise is indicated by a ΔmPAP/ΔCO slope of greater than 3 mmHg/L/min between rest and exercise. This response is associated with impaired prognosis in patients with exercise dyspnea and several cardiovascular diseases. Hypothesis: Our hypothesis was that pressure-flow relationship of the pulmonary circulation obtained by 6MW stress echocardiography would be enhanced with treatment. Aims: The aim of this study was to assess the effects of administration of Sacubitril/Valsartan on cardiac function in heart failure. Methods: We prospectively enrolled 39 patients with heart failure. The 6MW test was performed indoors in a flat, straight corridor. The peak tricuspid regurgitation jet, early diastolic transmitral flow velocity and early diastolic mitral motion were obtained by echocardiography post-6MW. We calculated the slope of ΔmPAP/ΔCO as a parameter of pulmonary hypertension. Follow-up echocardiographic studies were performed after 1 year. Results: Left ventricular diameter and volume were significantly reduced (LVDd; 59.3±7.7mm vs 56.0±8.6mm, P&lt;0.001, LVEDV; 160.7±49.6ml vs 136.0±54.3ml, P&lt;0.001), and LVEF was significantly improved (37.6±11.3% vs 44.9±11.5%, P&lt;0.001). Among the 31 patients who underwent 6MW stress echocardiographic study at baseline and 1 year later, 6MW distance increased after treatment (380m vs 430m, P=0.003). The ΔmPAP/ΔCO by 6MW stress decreased with treatment (6.9mmHg/L/min vs 2.8mmHg/L/min, P=0.002). Conclusions: Initiation of Sacubitril/Valsartan was associated with improvement of left ventricular size and LVEF. Additionally, the 6MW distance increased and the ΔmPAP/ΔCO was improved to within normal range with treatment. Sacubitril/Valsartan distinctly improved cardiac reactivity to exercise.